Targeting epithelial cells to treat pulmonary fibrosis

描述：该翻译计划项目资助旨在开发特发性肺纤维化（IPF）的新有效疗法。该基金完全专注于开发专门针对肺泡上皮细胞中已知通路的新药，这些通路对肺纤维化的发展至关重要。该基金还将使用一种新的、基于机制的方法来鉴定来自人类细胞和组织的信息性生物标志物，这些生物标志物将为我们在随后的IPF患者早期临床试验中开发的每种药物的有效性提供早期指标。该授权的基本原理是IPF是非持续性上皮应激和细胞凋亡的结果，其导致肺泡上皮细胞上的α-nu-β整合素激活细胞外潜伏的TGF β，这反过来至少诱导进行性纤维化。 部分通过诱导上皮细胞中的TGF β信号传导。该提案包括3个项目，每个项目将利用多个肺纤维化小鼠模型来评估现有药物的疗效，这些药物靶向上皮细胞中未折叠蛋白反应诱导的凋亡，整合素介导的TGF β激活和TGF β信号传导，并开发具有改善效力和降低全身毒性的新型药物。通过平行分析这些药物对人肺泡上皮细胞和人肺碎片的作用，这些项目将进一步评估小鼠研究结果对人类的适用性。每个项目还将利用来自IPF患者和健康对照的血液和BAL细胞和液体的系列样品来表征推定的生物信息生物标志物的效用和再现性。这些项目将得到人类肺细胞和组织核心、纵向队列核心、药物化学核心和集中管理核心的支持。通过对最有希望的候选药物进行广泛的临床前分析，确定其在人肺中的有效性，并开发可以在血液，支气管肺泡灌洗液或肺泡巨噬细胞中检测到的药物有效性的读数，所进行的工作应为计划的第二阶段中最有希望的候选药物的临床试验奠定基础。

DESCRIPTION: This translational program project grant is designed to develop new effective therapies for idiopathic pulmonary fibrosis (IPF). The grant is entirely focused on developing new drugs that specifically target known pathways in alveolar epithelial cells that are critical fo the development of pulmonary fibrosis. The grant will also use a novel, mechanism-based approach to identify informative biomarkers from human cells and tissues that should provide early indicators of the effectiveness of each of the drugs we develop in subsequent early phase clinical trials in patients with IPF. The rationale for this grant is that IPF is a consequence of n-going epithelial stress and apoptosis, which leads to activation of extracellular latent TGFbeta by the alpha nu beta integrin on alveolar epithelial cells, which in turn induces progressive fibrosis at least in part through induction of TGFbeta signaling in epithelial cells. The proposal includes 3 projects which will each utilize multiple mouse models of pulmonary fibrosis to evaluate the efficacy of existing drug agents that target apoptosis induced by the unfolded protein response, integrin-mediated TGFbeta activation and TGFbeta signaling in epithelial cells, and to develop novel agents with improved potency and reduced systemic toxicity. By parallel analysis of the effects of these drug agents on human alveolar epithelail cells and human lung fragments, these projects will further asess the applicability of murine findings to humans. Each project will also take advantage of serial samples of blood and BAL cells and fluid from patients with IPF and healthy controls to characterize the utiltiy and reproducibility of putative biologically informative biomarkers. These projects will be supported by a human lung cell and tissue core, a longitudinal cohort core, a mediciinal chemistry core and a centralized administrative core. By performing extenisve pre-clinical analysis of the most promising candidate drugs, establishing their effectiveness in human lung, and developing read-outs of drug effectiveness that can be detected in blood, bronchoalveolar lavage fluid or alveolar macrophages, the work performed should lay the groundwork for clinical trials of the most promising candidates in a planned second phase of this program.